A trigger for infection

Clinical Research Division study tracks common viruses and their connections to airflow obstruction in post-transplant population

Dec. 15, 2005

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By COLLEEN STEELQUIST

Dr. Michael Boeckh, of the Program in Infectious Disease, probes the depth of the connection between community-acquired respiratory viruses (CRVs) and asthma-like breathing difficulties in long-term stem-cell transplant survivors.

Photo by Todd McNaught

Common cold and flu ailments cause short-term misery for many people each winter. But for patients recovering from stem-cell transplants, these viruses can go beyond sniffles and body aches and turn deadly. Now an ambitious new Clinical Research Division study is taking aim at these garden-variety illnesses in an effort to better understand their contribution to significant breathing difficulties in some long-term survivors and to provide new targets for therapy.

The study looks at the correlation between ordinary respiratory viruses and an asthma-like condition called airflow obstruction. These run-of-the-mill illnesses — termed community-acquired respiratory viruses, or CRVs — are well recognized for sometimes leading to fatal pneumonia after stem-cell transplantation. But recent studies suggest that the impact of CRV infection on overall post-transplant survival may be far greater than previously thought. The researchers hope to determine how often CRVs are associated with the development of airflow obstruction, if the risk varies with different viruses and if the site of the infection in the upper or lower respiratory tract affects long-term health.

Dr. Michael Boeckh, principal investigator, Program in Infectious Disease, collaborates in the study with pulmonologist Dr. Jason Chien, also of the Clinical Research Division. In previous research, Chien found that up to 30 percent of long-term transplant survivors experience a significant, irreversible decline in their pulmonary airflow; patients with severe airflow obstruction have mortality rates that are more than twice as high as those without such breathing problems. It's long been thought that transplant-related airflow obstruction is a manifestation of graft-vs.-host disease alone, but Chien's preliminary data suggests that CRVs are also associated with the development of this complication.

"Seeing this link to airflow obstruction is a novel thing in stem-cell transplantation," Boeckh said. "Jason's research suggests that this late airflow decline is an independent risk factor for mortality. These people can get constant pulmonary infections. We want to look at viruses as a potential trigger of this. We have developed quantitative PCR-based diagnostic assays that allow us to test the virus load of CRVs with a very high level of sensitivity."

In healthy people, lung function declines about 1 percent each year. Chien conducted a smaller, earlier study that found an accelerated decline of more than 5 percent per year in some post-transplant populations. The current study, using quantitative molecular methods, looks at eight different viruses to determine how their occurrence correlates with late airflow obstruction.

The study began this month with plans to recruit 500 adult and pediatric Seattle Cancer Care Alliance patients over the next three years. The participants, who return to homes throughout the United States after their transplants, are asked to send weekly nasal-wash specimens to be tested for evidence of CRVs. Each member is trained in the use of a portable electronic spirometer, a device smaller than a TV remote-control, which measures pulmonary function and stores the information in its memory chip. Patients then send this device and their stored results via overnight mail. Patients are monitored for one year.

Study may aid future treatments

"Many investigators shy away from this type of long-distance research. They think it's too complicated, not feasible," Boeckh said. "But we are particularly interested in that time period when patients are back at home because this is when the biggest exposure occurs. They're still somewhat immunosuppressed, yet they are entering life again. This is what we want to capture."

Although Boeckh's study is strictly observational, it may become the basis for future intervention studies testing possible treatments.

"For now, influenza is basically the only virus we can treat with oral medications. So for this study, if our tests show influenza, the patients can go to their physicians and get treated, if they choose," Boeckh said.

Chien hopes the longitudinal look at viruses in this study will aid future treatments. "Although there are few treatments for CRVs, early detection is the first step toward understanding how viral infections damage the airways," he said. "Once we can identify patients early in the infection course, we will be able to design studies to understand the mechanisms by which this might occur, which will hopefully lead us to developing novel treatments for airways diseases related to CRVs."

A lifeline for patients

According to Boeckh, many patients appreciate the added connection to their cancer center provided by involvement in the study. "A significant number of patients — especially if they're returning to small communities — are grateful for that additional lifeline," he said. "Of course, they can contact our Long-Term Follow-Up staff with questions any time, but we actively call them throughout the study."

Chien agrees that Center patients often welcome extra follow-up. He previously initiated a research project to teach patients to monitor their own lung function using the same self-monitoring device. "The patients are very appreciative of being able to see how their lung function changes on a weekly basis and having a contact here at the Center to ask questions concerning their pulmonary function," he said.

Dr. Angela Peck, an Infectious Disease fellow, and Cara Varley, study coordinator, are responsible for the day-to-day operations of the $2.5 million NIH-funded study. Other Center collaborators include Drs. Larry Corey, Wendy Leisenring and David Madtes. Drs. Jane Kuypers and Rhoda Ashley Morrow, University of Washington, and Dr. Janet Englund, Children's Hospital and Regional Medical Center, also contributed to the study.